rs513043

Positions:

• chr1-156129878-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170707.4(LMNA):​c.357-739T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 769,892 control chromosomes in the GnomAD database, including 9,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4791 hom., cov: 32)
  • Exomes 𝑓: 0.090 (4327 hom.)
• Consequence: LMNA NM_170707.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.34

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017819703).
• BP6: Variant 1-156129878-T-G is Benign according to our data. Variant chr1-156129878-T-G is described in ClinVar as [Benign]. Clinvar id is 192190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156129878-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_005572.4	c.357-739T>G		intron_variant		ENST00000677389.1	NP_005563.1
LMNA	NM_170707.4	c.357-739T>G		intron_variant		ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.357-739T>G		intron_variant		1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.357-739T>G		intron_variant			NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27542 AN: 151952 Hom.: 4757 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.0943

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.100 AC: 22581 AN: 225092 Hom.: 2252 AF XY: 0.100 AC XY: 12364 AN XY: 123588

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.0650

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0565

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0937

GnomAD4 exome AF: 0.0904 AC: 55866 AN: 617822 Hom.: 4327 Cov.: 0 AF XY: 0.0928 AC XY: 31185 AN XY: 336006

Gnomad4 AFR exome AF: 0.466

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.0155

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.0545

Gnomad4 NFE exome AF: 0.0724

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.182 AC: 27624 AN: 152070 Hom.: 4791 Cov.: 32 AF XY: 0.179 AC XY: 13340 AN XY: 74338

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.0941

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0711

Gnomad4 OTH AF: 0.149

Alfa AF: 0.121 Hom.: 1263

Bravo AF: 0.196

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.450 AC: 788

ESP6500EA AF: 0.0721 AC: 287

ExAC AF: 0.101 AC: 11773

Asia WGS AF: 0.108 AC: 375 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hutchinson-Gilford syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	-0.0031
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	0.27	D
MutationTaster	Benign	0.74	P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.28
ClinPred		0.065	T
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs513043; hg19: chr1-156099669; COSMIC: COSV61543010; COSMIC: COSV61543010;